Serum albumin is the most abundant plasma protein in animal blood. In humans, human serum albumin (HSA) is present at an average concentration of about 45-50 mg/ml in plasma which corresponds to 52-65% of the total protein content. The molecular weight of HSA is 66,300, it is not glycosylated and has a half-life of about 17 days in the circulation.
Serum albumin acts as a carrier of fatty acid, bilirubin, hormones, drugs and metal ions by reversibly binding these agents. Albumin functions in the delivery of biologically relevant materials and scavenges waste materials for elimination. One of its major functions, associated with its high concentration, is to provide much of the osmotic pressure in blood that is required to balance the high concentration of osmotically active macromolecules in the cytoplasm of blood cells. In addition, a pressure balance must be maintained across the endothelium between the interior of blood vessels and the interstitial space to avoid undue water movement and tissue swelling (edema). HSA provides about 80% of the colloid osmotic pressure that balances the hydrostatic pressure in the vascular tree.
Replacement of serum albumin is particularly important in acute conditions such as burns, severe blood loss, cardiac surgery, shock or other conditions where potentially life threatening fluid shifts occur unless lost volume and osmotic activity are replaced.
One approach for production or improvement of a plasma protein is to produce it by recombinant techniques. This has been done for HSA but because of the large amounts required for clinical purposes worldwide, this approach is cost prohibitive.
For decades, attempts have been made to use various polymers as cost effective serum albumin substitutes. Polysaccharides (modified starch such as hydroxyethyl starch (HES) or dextran) and collagen (i.e., gelatin) derivatives have been used as plasma expanders. Solutions of such macromolecules (“colloids”), rely on molecular size for their ability to produce the desired osmotic gradient between plasma and interstitial space. However, all the synthetic colloids increase plasma viscosity significantly, which is detrimental to the heart and circulatory system and all the synthetic colloids have effects on whole blood rheology, including red cell aggregation. While dextran and HES are or have been used as substitutes for serum albumin with respect to plasma expansion, they increase plasma viscosity dramatically because of their broad molecular weight distribution and high average molecular weight (Mw about 670,000 for hetastarch). Buffered salt solutions (“crystalloids”) are also employed and are more cost effective than colloids, but they must be administered in much larger volumes and their effects are very short term. None of the polysaccharide or collagen based derivatives nor salt solutions perform any function of serum albumin other than its role in the maintenance of osmotic pressure.
Various polymers have also been used or proposed as drug delivery vehicles or as carriers for biologically active compounds. Such polymers have included dendritic polymers, including dendrimers and hyperbranched polymers such as hyperbranched polyglycerol (HPG) (for example see: Sunder, A., et al. (1999) Angew Chem. Int. Ed. 38:3552-55; international patent application publication WO 2004/072153; and United States patent application publication 2005/0048650). Linear polyethylene glycols have been used in drug delivery and have also been proposed for use in perfusates and solutions for organ and tissue preservation (e.g. see U.S. Pat. Nos. 6,321,909; 6,616,858; 6,949,335; United States patent application publications 2001/0037956 and 2006/0024657; and international patent application publication WO 2001/01774). In one publication, hyperbranched polymers containing a porphyrin core were proposed as hemoglobin substitutes (see international patent application PCT/GB2004/004841, now published as WO 2005/052023).